Making Headway Against Lou Gehrig's Disease

As many physicians are all too aware, the neuronal degeneration that occurs with amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, leads to progressive muscle weakening that eventually disables and kills these patients. Now, a rapidly deepening understanding of this process may offer ALS patients hope.

Implicated Protein, Accelerated Research

Over the past few years, a number of studies have indicated that the protein TDP-43, which in a benign form resides in the nuclei of cells, is a significant factor in the neurodegeneration associated with sporadic ALS. Furthermore, mutations in the gene encoding TDP-43 are responsible for a small proportion of familial ALS cases, confirming the integral contribution of this protein to the development of ALS.

In January 2010, a team at UCSF and its affiliated Gladstone Institute of Neurological Disease published a paper that provided a possible mechanism for neuronal loss caused by mutant TDP-43. The study found that, as opposed to its normal form, the mutant protein more often moves from the nucleus to the cytoplasm of affected neurons. This mislocation is a key pathological characteristic of the disorder in humans.

The study arrived at this finding by using a technique called automated fluorescence microscopy, which was developed by UCSF neurologist Steven Finkbeiner, M.D., Ph.D. By tagging both normal and mutant TDP-43 proteins in cultured rat cortical neurons, researchers could view their intracellular locations and follow them until they died. The same team is now using induced pluripotent stem cells derived from human ALS patients to conduct a similar study.

Sami Barmada, M.D., Ph.D., one of the project’s lead researchers, said, "The automated fluorescence microscopy is enormously powerful because we can follow the fate of hundreds of thousands of neurons in a very contained period of time. And the advantage of using induced pluripotent stem cells from human ALS patients is that we can differentiate them into the type of neurons we know are involved in ALS."

Therapies for ALS and Beyond

Barmada noted that numerous questions have yet to be addressed. Among the most important:

Which characteristics of the cells allow them to live longer?

Which characteristics are associated with early cell death?

What causes the toxicity of the mutant TDP-43?

"We do know, however, that in rats we have prevented the toxicity by genetic means, by disrupting the nuclear export signal of the mutant protein and thereby forcing it to remain within the nucleus,” Barmada said. "A possible alternative strategy for mitigating the toxicity is to accelerate its degradation within the cytoplasm through pharmacologic means."

The work has implications that go beyond ALS because the mutant TDP-43 also is associated with the memory disorder frontotemporal dementia. "If we conclusively find what's important for cell death in these disorders, we would be in a great position to prevent the process from happening, and even reverse it," Barmada said.

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